Babu G. Sundar

Identification of pyridazin-3-one derivatives as potent, selective histamine H3 receptor inverse agonists with robust wake activity

H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model.

Amine-constrained pyridazinone histamine H3 receptor antagonists

Pyridazinone 1 was recently reported as a potent H(3)R antagonist with good drug-like properties and in vivo activity. A series of constrained amine analogs of 1 was synthesized to identify compounds with improved pharmacokinetic profiles. From these efforts, a new class of (S)-2-pyrrolidin-1-ylmethyl-1-pyrrolidinyl amides was identified.

Novel morpholine ketone analogs as potent histamine H3 receptor inverse agonists with wake activity

Structure-activity relationship on a novel ketone class of H(3)R antagonists/inverse agonists is disclosed. Compound 4 showed excellent target potency, selectivity and brain penetration. Evaluation of antagonist 4 in the rat EEG/EMG model demonstrated robust wake activity thereby establishing preclinical proof of concept.

Novel brain penetrant benzofuropiperidine 5-HT6 receptor antagonists

7-Arylsulfonyl substituted benzofuropiperidine was discovered as a novel scaffold for 5HT(6) receptor antagonists. Optimization by substitution at C-1 position led to identification of selective, orally bioavailable, brain penetrant antagonists with reduced hERG liability. An advanced analog tested in rat social recognition model showed significant activity suggesting potential utility in the enhancement of short-term memory.

1-Phenyl-2-pyrrolidinyl-cyclopentylamine via Thermal Rearrangement

Abstract Thermal rearrangement of aminoimine, 1, followed by hydrogenation produced 1-phenyl-2-pyrrolidinyl cyclopentylamine 3. The structure and stereochemistry of this novel amine 4 was identified by x-ray crystallography of the 2-chloro-6-iodo-nicotinamide derivative as a hydrogen maleate salt.